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Targeting USP7 as a novel therapeutic approach in drug resistant Non-Hodgkin lymphoma (NHL).

School of Medicine, Dentistry and Biomedical Sciences | PHD

Applications are now CLOSED
Funding
Funded
Reference Number
SMED-2241-1030
Application Deadline
10 April 2024
Start Date
1 October 2024

Overview

Chemotherapy resistance represents a major challenge in cancer therapy. This is a significant problem in Non-Hodgkin lymphoma (NHL), which arise in B-cells and lymphoid tissues and are amongst the most common cancers. One important observation made in B-cell lymphomas, is that they have a high frequency of mutations in a gene called EZH2, which plays a crucial role in controlling the chemical modification of chromatin. Accordingly, a drug that inhibits EZH2 function has been recently approved by FDA as a promising therapy in NHL. However, lymphoma cells that have prolonged treatment with the EZH2-inhibitor drug develop resistance. Therefore, there is an urgent need to investigate additional strategies to combat resistance to EZH2-inhibitor in lymphomas. In this PhD project, we will use state-of-the-art epigenomics and CRISPR/Cas9 approaches to characterize mechanisms of drug resistance in B-cell lymphomas and investigate novel strategies to combat the resistance to EZH2 inhibitor drugs.

Mutations in chromatin regulators are widespread in cancer and can lead to epigenetic dysregulation. For example, mutations in a chromatin regulator called EZH2 are common in Non-Hodgkin lymphoma (NHL), leading to hyperactivity of EZH2 protein and aberrant silencing of target genes. Accordingly, an EZH2 inhibitor drug called Tazemetostat, has been approved for the treatment of patients with NHLs. However, resistance to this drug has been reported. The overall objective of this research project is to develop and investigate innovative strategies to treat lymphoma cells that acquire resistance to EZH2 inhibitors. EZH2 is a member of the Polycomb Repressor Complex 2 (PRC2) that deposits the H3K27me3 repressive histone. PRC2 collaborate with another chromatin regulator called PRC1 to silence gene expression. We have recently discovered that the levels of PRC1 protein complex is stabilized by a gene called USP7. USP7 removes the ubiquitin group from target proteins, leading to stabilization of client proteins. Accordingly, inhibiting USP7 using a small molecule inhibitor leads to reduction in PRC1 level and activation of target genes (Science Advances 2022). USP7 has emerged as a crucial player in cancer that can be targeted by selective inhibitors, some of which have been developed in collaboration with QUB researchers. Our discovery has led us to hypothesize that targeting the USP7-PRC1 axis can activate target genes in lymphoma cells that are responsive to EZH2/PRC2 inhibitors, providing an alternative approach to prevent or overcome drug resistance. Indeed, our pilot data have demonstrated that USP7 inhibition is a promising therapeutic approach for treating drug-resistant lymphoma. In this research, we will utilize genomics and CRISPR/Cas9 approaches to characterize the molecular response to USP7-inhibition in drug-resistant lymphomas. Furthermore, we will utilize pre-clinical models of B-cell malignancies to clarity the therapeutic potency of USP7i, providing a rational for translating these findings into the clinic.

We seek a highly motivated and ambitious candidate with a general background in cancer biology, molecular biology, or cell biology. The candidate will receive extensive training in cell and molecular biology, genomics, and basic bioinformatics. The PhD student will receive direct supervision from the PIs and a senior postdoc and will closely work with PhD students within the epigenetic and blood cancer groups. Additionally, the PhD student will have the opportunity to enhance their skills in cell and molecular biology techniques by visiting our collaborative laboratories in Europe.

Funding Information

This is a competitive award, there are five advertised projects for two studentship awards

To be considered eligible you must have been ordinarily resident in the UK for the full 3-year period prior to the start of the studentship and you must be ordinarily resident in Northern Ireland on the first day of the start of the studentship. If successful, support will be provided by an LLNI studentship.

The value of an award includes the cost of approved tuition fees and maintenance support, rates for 2024/25 are Fees £4,786, Stipend £19,479 with an inflationary uplift in subsequent years.

Project Summary
Supervisor

Dr Yaser Atlasi

Research Profile

Mode of Study

Full-time: 3 Years

Funding Body
LLNI
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